One of the most dramatic but least understood examples of cell death is thyroid hormone (TH)-induced tail resorption during amphibian metamorphosis. Matrix metalloproteinases (MMPs) play a role in tail resorption and organ remodeling, although it is not clear whether different tail cell types are killed by these proteases or if they die autonomously by a TH-induced suicide. Don Brown's lab has identified twenty-one TH-regulated genes during tadpole (Xenopus laevis) tail resorption, including two MMPs (collagenase-3 and stromelysin-3) and a member of the dipeptidyl peptidase family (fibroblast activation protein alpha) expressed in primary carcinomas. Two of these genes and a TH- regulated cell membrane receptor (integrin alpha-1) are co-expressed in invasive fibroblasts which surround the notochord and muscle flank. The goals of this research proposal are to determine the influence of these TH- responsive genes and of MMP activity on cell death in the epidermis and muscle during tadpole tail influences of these TH-responsive genes and of MMP activity on cell death in the epidermis and muscle during tadpole tail resorption. The possibility that cells in the epidermis and muscle die autonomously in response to TH will be tested by using a new transgenic procedure to over-express dominant negative TH-receptors (dnTR) using tissue-specific promoters in an attempt to inhibit cell death during metamorphic climax. The influence of MMP activity on death of these tissues will be addressed by inhibiting TH-responsive proteases with dnTR over-expression using promoters which drive in fibroblasts, and also by over-expressing a tissue inhibitor of metalloproteinases (TMP) during climax. The specificity and functionality of various promoters driving these genes will be tested in vivo through transgenic expression of the clines linked to reporter genes. The induction of Xenopus tail resorption by TH provides a unique experimental model system from which to determine the functions of tissue-specific regulatory proteins which may play important roles in post-embryonic development.